Nucleic acids are used as therapeutics, for example, in oligotherapy, antisense therapy, siRNA, and RNAi. However, nucleic acids have low cellular penetration of the nucleic acid. Antisense based therapies, for example, rely on the hybridization to complementary sequences, to allow for the selective silencing of particular genes. Thus, oligotherapeutics is a very attractive approach for the treatment of cancer, genetic mutations, and even microorganism-mediated diseases.
The main hurdle in achieving the potential therapeutic advantages of these approaches included poor stability of the oligonucleotides and inefficient intracellular penetration of the oligonucleotides. This prompted the development of a large number of synthetic analogs of natural oligonucleotides, such as 2′-position modifications, boranophosphonates, locked nucleic acids, peptide nucleic acids (PNA), morpholino derivatives, alkynyl phosphonates, and terminally modified oligonucleotides. While these modifications improved the biological stability, they did not change the intracellular penetration of oligonucleotides.
To overcome these challenges, different vehicles have been proposed such as virus-based delivery systems, liposome formulations, nanoparticles, and transporter chemical groups. For example, tagging the ends of siRNAs with cholesterol, folate, various peptides, and aptamers can aid in transporting oligonucleotides across cellular barriers or in targeting specific type of cells or organs.
One widely used modification of oligonucleotides is the attachment of amino groups to oligonucleotides via linkers, mostly used as anchor groups for post-synthetic derivatization of synthetic oligonucleotides. The linker is usually attached to the 5′-end of the oligonucleotide upon the completion of automated synthesis. Attachment to the 3′-end on non-standard supports has also been explored. Attachment of linkers to the internucleotide phosphates has been performed as well.
However, despite the development of a large number of chemical modifications of oligonucleotides including different delivery systems, the absence of available oligonucleotides having effective cellular uptake remains an unmet need. Accordingly, there is a need for compositions, compounds and systems for modified oligotherapeutics and to enhance the cellular uptake of oligonucleotides for the treatment of diseases and disorders.